1,2-Dihydro- and 1,2,3,4-tetrahydro-1-oxo-3-isoquinolinecarboxylic acid derivatives as anti-allergic agents

ABSTRACT

Atopic allergic reactions, such as hives asthma, hay fever, allergic rhinitis, urticaria, conjunctivitis, food allergies, and the like, are prevented in a sensitive, warm-blooded animal by administration of a compound of the formula:   IN WHICH R1 is -H alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxyalkoxy of 2 to 6 carbon atoms, halo, -NO2, -NH2, dialkylamino having from 1 to 6 carbon atoms in each alkyl group, -CONH2, -SO2NH2, carbalkoxy having from 2 to 6 carbon atoms or alkylthio of 1 to 6 carbon atoms; and R2 is -H, alkyl of 1 to 6 carbon atoms, an alkali metal cation or the ammonium cation, WHEREIN THE DOTTED LINE APPEARING IN THE STRUCTURAL FORMULA REPRESENTS OPTIONAL UNSATURATION.

United States Patent [191 Sellstedt et al.

[73] Assignee: American Home Products Corporation, New York, NY.

[22] Filed: Oct. 2, 1974 [21] Appl. No.: 511,341

[52] US. Cl. 424/258 [51] Int. Cl. A61K 31/47 [58] Field of Search424/258 [56] References Cited OTHER PUBLICATIONS Cohen, et al., J.Biological Chemistry 5/25/68, 243,

No. 10, pp. 2607-2617.

Chemical Abstracts 64:697(a), (1966). Chemical Abstracts 76:l5047l(n),(1972). Chemical Abstracts 67:90637(g), (1967). Chemical Abstracts 65:15317(f), (1966). Chemical Abstracts 76:82825(d), (1972) PrimaryExaminer-Norman A. Drezin Attorney, Agent, or FirmRichard K. JacksonDec. 23, 1975 [57] ABSTRACT Atopic allergic reactions, such as hivesasthma, hay fever, allergic rhinitis, urticaria, conjunctivitis, foodallergies, and the like, are prevented in a sensitive, warm-bloodedanimal by administration of a compound of the formula:

in which R is H alkyl of l to 6 carbon atoms, alkoxy of l to 6 carbonatoms, hydroxyalkoxy of 2 to 6 carbon atoms, halo, -NO -NH dialkylaminohaving from 1 to 6 carbon atoms in each alkyl group, -CONl-l -SO NHcarbalkoxy having from 2 to 6 carbon atoms or alkylthio of l to 6 carbonatoms; and R is --H, alkyl of l to 6 carbon atoms, an alkali metalcation or the ammonium cation, wherein the dotted line appearing in thestructural formula represents optional unsaturation.

7 Claims,No Drawings 1,2-DII-IYDRO- AND l,2,3,4-TETRAHYDRO-1-0XO-3-ISOQUINOLINECARBOXYLIC ACID DERIVATIVES AS ANTI-ALLERGIC AGENTSDESCRIPTION OF THE INVENTION In accordance with this invention, there isprovided a method for preventing the physical manifestations of atopicimmediate sensitivity resulting from attacks of in which R is H, alkylof 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hyroxyalkoxy of 2to 6 carbon atoms, halo, -NO NH dialkylamino having from 1 to 6 carbonatoms in each alkyl group, CONH SO NH carbalkoxy having from 2 to 6carbon atoms or alkylthio of l to 6 carbon atoms; and R is H, alkyl of 1to 6 carbon atoms, an alkali metal cation or the ammonium cation,wherein the dotted line appearing in the structural formula representsoptional unsaturation.

The preferred anti-allergies of this invention from the standpoint ofproduction economics and pharmacological activity levels present thestructural formula:

in which R is H or alkoxy of 1 to 6 carbon atoms; and

R is H, alkyl of 1 to 6 carbon atoms or an alkali metal cation,

wherein the dotted line appearing in the structural formula representsoptional unsaturation.

In addition, there is provided by this invention, certain novelanti-allergic compounds of the formula:

OFU

in which R is alkyl of 1 to 6 carbon atoms; and

R is H, alkyl of 1 to 6 carbon atoms, an alkali metal cation or theammonium cation.

Atopic hypersensitivity, as found typically in man, dog and other highermammals, occurs exceptionally in the lower animals, and is mostfrequently caused by inhalation or ingestion of substances such as plantpollen, animal feathers and danders, dust, milk, wheat and similarpoisons or irritants.

The presence of antibodies associated with atopic reactions in the hostserum is established by passive sensitization of the skin of a normalrecipient, after injection of serum from a sensitized host into a skinsite followed by injection of antigen into the same skin area twentyfour hours later, producing a local hive. This is commonly referred toas the Prausnitz-Kustner (P-K) reaction.

The antibody associated with atopic hypersensitivity possessesdistinctive features in that it does not in all forms precipitate withits antigen, fails to pass the placenta from mother to fetus, hasspecial affinity for the skin, frequently lacks specificity toward anindividual antigenic factor and is usually labile at about 56C. aftertwo hours.

The homocytotropic antibody found in or induced in the rat is relatd infunction and reaction to immunoglobulin E (reagin or IgE) found in thehuman. The functional correlation between homocytotropic antibody in therat and IgE in the human has been established through their commoneffects obtained from chemical reactions, immunological reactions anddrug responses in the two species hosting those antibodies. In thehuman, reagin is the antibody responsible for atopic immediatehypersensitive reactions, while homocytotropic antibody is thecorresponding antibody in the rat responsible for atopic immediatehypersensitive reactions. Based upon the functional correlation betweenthe homocytotropic antibody in the rat, similar antibodies in the dog,and IgE in the human, effects obtained in the rat as the standardexperimental animal are extrapolatable to higher animals such as the dogand man.

In theory, reagin influences the cell membrane of a mast cell byreacting with an antigen to initiate the reaction(s) within the mastcell which ultimately releases a mediator such as Bradykinin, SRS-A(slow reacting substance-A), histamine and other unknown substances. Themediator effects a change in surrounding cell wall penneabilitypermitting a rapid change in flow or exudance of mediator(s) from thecells, resulting in an allergic attack symptom. Various methods arecommonly employed to relieve the symptoms of allergic attack, none ofwhich are quite acceptable, including (1) avoid the attack by theantigen, (2) block the production of antibody with an immunosuppressant,(3) block the action of the mediators on the cell under attack byadministration of anti-histaminics, anti-5- hydroxy tryptamine (S-HT) orantiinflammatories or (4) stimulate the cell under attack to negate theaction of the mediator through the action of bronchodilators such aslsoprel or a Xanthine.

Although the specific type of activity elicited from administration of1-oXo-3-isoquinoline carboxylic acid derivatives as herein disclosed isnot known, it is be lieved that the reaction(s) within the mast cellsare blocked, thereby preventing production and release of mediators, ina manner similar to the activity of 1N- TAL, which permits theoccurrence of non-productive antigenantibody interaction in the mastcell without formation of mediators.

In practice, the l-oxo-3-isoquinolinecarboxylic acid derivatives areadministered parenterally to the sensitized animal prior to an allergicattack in an amount necessary to obtain the desired response, whetherpartial or complete relief is desired, in single or plural dosesinitially under the guidance of medical assistance for the purpose ofdetermining the optimum dosage for the specific animal being treated.The efi'ective dose range in test animals is between about 5 to 200milligrams per kilogram within which range, the doseresponse curvefavors treatment with from about 5 to about 100 milligrams per kilogramhost body weight. Thus, for veterinary use, such as in the dog, the sizeof the specific animal being treated dictates the proper dose size. Ifdesired, the compounds of this invention may be administered inconjunction with known compounds effecting antihistaminic,anti-hypertensive, analgesic, central nervous system depressant,immunosuppressive, anti-serotonin, anti-Bradykinin or endocrinologicalresponses. In addition, those conventional adjuvants known to the artmay be combined with the anti-allergics of this invention to providecompositions and solutions for administrative purposes, although it isconsidered desirable and feasible to employ the antiallergics as neat orpure compounds without additives other than for purposes of providingsuitable pharmaceutical solution or liquid or vapor suspensions.

The 1,2-dihydro and l,2,3,4-tetrahydro-l-oxo-3- isoquinolinecarboxylicacid derivatives are produced by known methods. Thus, for example, anappropriately n'ng substituted 2-carbomethoxy benzaldehyde CO CH CHOwhich yields 1,2-dihydro-l-oxo-3-isoquinolinecarboxy- 6 lie acid upontreatment with potassium hydroxide. The

free carboxylic acid is converted to an ester or salt by conventionalmethods. If desired, the group R may be introduced as a ring substituentafter the l,2- dihydro-loxo-3-isoquinoline ring is formed, by carryingan appropriately reactive group through the ring closure in theillustrated 8-position (or the desired position) for the subsequentsubstitution reaction.

The l,2,3,4-tetrahydrol -oxo-3-isoquinoline carboxylic acid derivativesare produced by esterification of phenylalanine, conversion of the aminogroup to an isocyanato group with phosgene in the presence of an acidacceptor and ring closure with aluminum chloride. The aromatic ringsubstituent R may be present during the ring closure or introducedsubsequently by known methods.

EXAMPLE I l ,2-Dihydrol -Oxo-3-Isoquinolinecarboxylic Acid Sodium SaltThis compound is known in the chemical literature and is prepared by themethod of: D. Bain, W. H. Perkin and R. Robinson, J. Chem. Soc., 105,2392 (1914). The sodium salt is prepared from the acid (2.72 g., 0.0144mole) by addition of 14.40 ml. of 1.000 N sodium hydroxide to asuspension of the acid in ml. water. The solution is filtered and thefiltrate is freeze dried, giving 3.1 g. of the salt, mp. 300 C.

Analysis for: C H NNaO 0.85H O. Calculated: C, 53.0; H, 3,42; N, 6.18; HO,6.80. Found: C,52.57; H, 2.97; N,6.85; H O, 6.05.

Sodium l ,2-dihydrol-oxo-3-isoquinolinecarboxylate was administeredintraperitoneally at a dose of 200 milligrams per kilogram body weightto each of four male Charles River rats (200-250 grams body weight)which had been treated twenty four hours earlier by intracutaneousinjection of sera from rats immunized with egg albumin and pertussisvaccine. Five minutes later, one milliliter of a 0.5 percent solution ofEvans blue dye and eight milligrams of egg albumin were introducedintravenously to each animal. After forty minutes the bleb size formedat the skin site of the prior intracutaneous injection was measured. Themean bleb size for the four animals demonstrated a reduction of 60percent over that of a four rat control group simultaneously treated inthe same manner except for administration of the anti-allergic compound.

EXAMPLE 2 1 ,2,3,4-Tetrahydrol -Oxo-3-lsoquinolinecarboxylic Acid,Methyl Ester This compound is known in the chemical literature and isprepared by the method of S. Cohen and R. Schultz, J. Biol. Chem., 243,(10), 2607-2617 (1968).

Following the identical procedure of the preceding example, methyl 1,2,3,4-tetrahydrol-oxo-3- isoquinolinecarboxylate was administered tofour male Charles River rats, resulting in a 76 percent inhibition ofbleb size in comparison to the control group.

EXAMPLE 3 8-Methoxyl ,Z-Dihydrol -Oxo-3-lsoquinolinecarboxylic Acid Theappropriate phthalaldehydic acid ester is in the literature: F. Bohlmannand K. Prezewowsky, Chem. Ber., 97, 1178 (1964).

This ester is condensed with hippuric acid and hydrolyzed to the desiredcompound as in Example 1.

The anti-allergic activity of the title compound is elicited byadministration in accordance with Example 1.

EXAMPLE 4 8-Ethoxyl ,2-Dihydrol -Oxo-3-lsoquinolinecarboxylic Acid2-Bromo-m-cresol is alkylated using diethyl sulfatesodium hydroxide.This ethyl ether is then converted to the phthalaldehydic ester by themethod of Elie], et al., J. Org. Chem., 18, 1684 (1953).

The isoquinoline is prepared as in Example 1.

The anti-allergic activity of the title compound is elicited byadministration in accordance with Example 1.

What is claimed is:

l. A method for preventing the physical manifestations of an atopicallergic reaction which comprises parenterally administering to awarm-blooded animal in need thereof, an effective amount of a compoundof the formula:

in which R is -H, alkyl of l to 6 carbon atoms, alkoxy of l to 6 carbonatoms, hydroxyalkoxy of 2 to 6 carbon atoms, halo, -NO NH dialkylaminohaving from 1 to 6 carbon atoms in each alkyl group, COHN SO NHcarbalkoxy having from 2 to 6 6 carbon atoms or alkylthio of l to 6carbon atoms; and R is ---H, alkyl of l to 6 carbon atoms, an alkalimetal cation or the ammonium cation,

5 wherein the dotted line appearing in the structural formula representsoptional unsaturation.

2. The method of claim 1 which comprises parenterally administering tosaid warm-blooded animal, an effective amount of a compound of theformula:

in which R is -H or alkoxy of l to 6 carbon atoms; and R is H, alkyl of1 to 6 carbon atoms or an alkali metal cation, wherein the dotted lineappearing in the structural formula represents optional unsaturation.

3. The method of claim 1 which comprises administering to saidwarm-blooded animal the compound 1 ,Z-dihydrol-oxo-3-isoquinolinecarboxylic acid.

4. The method of claim 1 which comprises administering to saidwarm-blooded animal to compound sodium 1,2 -dihydro- 1-oxo-3-isoquinolinecarboxylate.

5. The method of claim 1 which comprises administering to saidwarm-blooded animal the compound methyl 1 ,2,3 ,4-tetrahydrol-oxo-3-isoquinolinecarboxylate.

6. The method of claim 1 which comprises administering to saidwarm-blooded animal the compound S-methoxyl ,Z-dihydrol-oxo-3-isoquinolinecarboxylic acid.

7. The method of claim 1 which comprises administering to saidwarm-blooded animal the compound 8-ethoxyl ,Z-dihydrol-oxo-3-isoquinolinecarboxylic acid.

1. A METHOD FOR PREVENTING THE PHYSICAL MANIFESTATIONS OF AN ATOPICALLERGIC REACTION WHICH COMPRISES PARENTERALLY ADMINISTERING TO AWARM-BLOODED ANIMAL IN NEED THEREOF, AN EFFECTIVE AMOUNT OF A COMPOUNDOF THE FORMULA:
 2. The method of claim 1 which comprises parenterallyadministering to said warm-blooded animal, an effective amount of acompound of the formula:
 3. The method of claim 1 which comprisesadministering to said warm-blooded animal the compound1,2-dihydro-1-oxo-3-isoquinolinecarboxylic acid.
 4. The method of claim1 which comprises administering to said warm-blooded animal to compoundsodium 1,2-dihydro-1-oxo-3-isoquinolinecarboxylate.
 5. The method ofclaim 1 which comprises administering to said warm-blooded animal thecompound methyl 1,2,3,4-tetrahydro-1-oxo-3-isoquinolinecarboxylate. 6.The method of claim 1 which comprises administering to said warm-bloodedanimal the compound 8-methoxy-1,2-dihydro-1-oxo-3-isoquinolinecarboxylicacid.
 7. The method of claim 1 which comprises administering to saidwarm-blooded animal the compound8-ethoxy-1,2-dihydro-1-oxo-3-isoquinolinecarboxylic acid.